Department of Microbiology, B103 Chemical and Life Science Building, 601 South Goodwin Avenue, University of Illinois, Urbana, IL 61801, USA.
Department of Microbiology, B103 Chemical and Life Science Building, 601 South Goodwin Avenue, University of Illinois, Urbana, IL 61801, USA.
Virus Res. 2018 Feb 15;246:55-64. doi: 10.1016/j.virusres.2018.01.004. Epub 2018 Jan 16.
Modified Vaccinia virus Ankara (MVA) is an attenuated Vaccinia virus (VACV) that is a popular vaccine vector candidate against many different pathogens. Its replication-restricted nature makes it a safe vaccine. However, higher doses or multiple boosts of MVA are necessary to elicit an immune response similar to wild-type VACV. Multiple strategies have been used to create modified MVA viruses that remain safe, but have increased immunogenicity. For example, one common strategy is to delete MVA immunomodulatory proteins in hopes of increasing the host immune response. Here, we take the opposite approach and examine, for the first time, how re-introduction of a 5.2 kb region of VACV DNA (that codes for multiple immunomodulatory proteins) into MVA alters viral immunogenicity. Since antigen presenting cells (APCs) are critical connectors between the innate and adaptive immune system, we examined the effect of MVA/5.2 kb infection in these cells in vitro. MVA/5.2 kb infection decreased virus-induced apoptosis and virus-induced NF-κB activation. MVA.5.2 kb infection decreased TNF production. However, MVA/5.2 kb infection did not alter APC maturation or IL-6 and IL-8 production in vitro. We further explored MVA/5.2 kb immunogenicity in vivo. VACV-specific CD8 T cells were decreased after in vivo infection with MVA/5.2 kb versus MVA, suggesting that the MVA/5.2 kb construct is less immunogenic than MVA. These results demonstrate the limitations of in vitro studies for predicting the effects of genetic manipulation of MVA on immunogenicity. Although MVA/5.2 kb did not enhance MVA's immunogenicity, this study examined an unexplored strategy for optimizing MVA, and the insight gained from these results can help direct how to modify MVA in the future.
改良安卡拉痘苗病毒（MVA）是一种减毒痘苗病毒（VACV），是针对许多不同病原体的流行疫苗载体候选物。它的复制受限性质使其成为一种安全的疫苗。然而，为了引起类似于野生型 VACV 的免疫反应，需要更高剂量或多次加强 MVA。已经使用了多种策略来创建具有安全性但免疫原性增加的改良 MVA 病毒。例如，一种常见的策略是删除 MVA 免疫调节蛋白，希望增加宿主免疫反应。在这里，我们采取相反的方法，首次研究了重新引入 VACV DNA 的 5.2kb 区域（编码多种免疫调节蛋白）如何改变病毒的免疫原性。由于抗原呈递细胞（APC）是先天免疫和适应性免疫系统之间的关键连接，因此我们在体外研究了 MVA/5.2kb 感染对这些细胞的影响。MVA/5.2kb 感染降低了病毒诱导的细胞凋亡和病毒诱导的 NF-κB 激活。MVA.5.2kb 感染减少了 TNF 的产生。然而，MVA/5.2kb 感染并未改变 APC 的成熟或体外的 IL-6 和 IL-8 产生。我们进一步探讨了 MVA/5.2kb 在体内的免疫原性。与 MVA 相比，体内感染 MVA/5.2kb 后，VACV 特异性 CD8 T 细胞减少，表明 MVA/5.2kb 构建体比 MVA 的免疫原性低。这些结果表明，体外研究对于预测 MVA 遗传操作对免疫原性的影响存在局限性。尽管 MVA/5.2kb 没有增强 MVA 的免疫原性，但本研究考察了一种优化 MVA 的未探索策略，从这些结果中获得的见解可以帮助指导未来如何修饰 MVA。
